Adenosine A2A receptor antagonists for treating restless legs syndrome or nocturnal myoclonus

ABSTRACT

The present invention provides methods of treating restless legs syndrome or related disorders, comprising administering an effective amount of at least one adenosine A 2A  receptor antagonist to a patient in need thereof. More preferably the adenosine A 2A  receptor antagonist is a xanthine derivative or a pharmaceutically acceptable salt thereof.

FIELD OF THE INVENTION

The present invention relates to methods of treating restless legssyndrome or related disorders. The method of treatment is preferably byadministering a pharmaceutical agent containing a therapeuticallyeffective amount of an adenosine A_(2A) receptor antagonist. Morepreferably the adenosine A_(2A) receptor antagonist is a xanthinederivative. Most preferably, the adenosine A_(2A) receptor antagonist isa xanthine derivative described in detail herein.

BACKGROUND OF THE INVENTION

Restless Legs Syndrome

Restless legs syndrome (RLS) is a distinctive but often misdiagnosedsensorimotor disorder. The general incidence of RLS is high and is theseventh most frequently diagnosed musculoskeletal disorder out of 103diagnoses relating to these conditions [Arch. Intern. Med., 161, 483-484(2001)]. RLS is also characterized as a sleep disorder and is frequentlydiagnosed as a cause of insomnia [Sleep Med., 2, 367-369 (2001); andSleep, 23, 237-241 (2000)].

Although RLS was first described in the 17^(th) century, the classicfeatures that define the syndrome were first presented in 1945 [TheLondon practice of Physick. London: Bassett et al. Eds. (1962); and ActaMed. Scand. Suppl., 158, 1-123 (1945)]. Despite the number of yearssince RLS was first appreciated as a medical indication, diagnosis andtreatment remain sub-optimal. Even though it may affect up to 10% of theUS population, it is often unrecognized or misdiagnosed. In some cases,a cause can be found, such as iron-deficiency anemia, and the RLS can becured. In general, however, motor restlessness is poorly diagnosed andtreated [IJCP, 55, 320-322 (2001)].

Although the etiology of RLS is unknown, the primary anatomiclocalization of abnormal functioning in RLS is possibly in spinal system[Disord., 13(suppl 2), 294 (1998)]. Several new diagnostic tools may aidin identifying RLS [J. Neurol., 249, 164-170 (2002); and Clin.Neurophys., 113, 571-578 (2002)].

The features associated with RLS include dysesthesias deep in the limbthat compel the person to move in order to relieve the sensation andthat are engendered and exacerbated by rest, primarily in the eveningand at night [HealthNews, Greene, Jun., 10 (2001)]. In 1995, theInternational RLS Study Group published the primary and associatedfeatures of this disorder [Mov. Dis., 10, 634-642 (1995)]. For recentreviews, see, Latorre & Irr (2001)http://www.emedicine.com/NEURO/topic509.htm; 2001 Medical Bulletin,Restless Legs Syndrome Foundation, Inc.; and Am. J. Med. Sci., 319,397-403 (2000). Additional criteria of RLS include involuntary, rhythmicretraction movements occurring especially at night, and especiallyduring sleep stages I and II; and sleep disturbance results in daytimefatigue.

Although RLS occurs as a component of several diseases, it is notindicative of these diseases [Sleep, 23, 361-367 (2000); Arch. Neurol.,59, 421-424 (2002); J. Neurol. Sci., 196, 33-36 (2002); and J. Neurol.Neurosurg. Psych., 72, 555 (2002)].

According to the Restless Legs Syndrome Foundation (www.rls.org), adultswith RLS will typically have all four of the following primary features.First, the bothersome, but usually not painful, sensations deep in thelegs produce an irresistible urge to move. Second, symptoms are worse orexclusively present when the afflicted individual is at rest, and thesensations are typically lessened by voluntary movement of the affectedextremity. Third, symptoms are worse in the evening and at night,especially when the individual lies down. Fourth, movements of the toes,feet, or legs (known as restlessness) are typically seen when theafflicted individual is sitting or lying down in the evening. Thisrestlessness may be seen as fidgetiness or nervousness.

The dysesthesias and accompanying urge to move occur most commonlyduring the evening or early part of the night (between 6 pm and 4 am)[Sleep, 22, 901-912 (1999); and Mov. Disord., 14, 102-110 (1999)].Patients are less bothered by symptoms during the daytime and, even ifseverely affected, often obtain some relief near dawn. The symptomsprogress over time in about two thirds of RLS patients and may be severeenough to be disabling, disrupting sleep and impacting on a patient'slife and well-being.

Adults with RLS almost always describe these uncomfortable sensations orparenthesis, which most commonly occur in the legs, as being like anelectric current, water moving, or insects crawling or as tingling,aching, or grabbing. A wide variety of other descriptions have beenoffered, and some patients cannot describe the sensations at all exceptas an urge to move the leg [Neurol., 47, 1435-1441 (1996)].

In a significant minority of individuals with RLS (perhaps 20% to 30%),similar sensations occur in the arms, usually in more severely affectedpatients later in the clinical course of their disorder [Eur. Neurol.,45, 67-74 (2001); and Eur. Neurol., 44, 133-138 (2000)]. Even lessfrequently, these sensations occur in the trunk or elsewhere. Thesensations are not generally described as painful, but if askeddirectly, a minority (perhaps 20%) of patients will describe thesensations as painful.

The unpleasant limb sensations of RLS are precipitated by rest orinactivity such as lying in bed, riding in a car or airplane or sittingin a theater. Some patients describe increasing discomfort andinvoluntary limb jerking if they remain still. There is an urge to movethe legs because relief is often gained after moving. To relieve theurge to move, patients typically walk around, although they may attemptto obtain relief through performing a wide variety of movements such asrocking, shaking, stretching, marching in place, pacing, or bending.Some patients obtain relief simply from standing.

These varied movements that patients select to reduce their symptoms areunder voluntary control and can be suppressed on command. Suppressionmay greatly increase the patient's discomfort, however, and few severelyaffected individuals are capable of stifling their restless movementsfor more than a brief period when they are symptomatic. In rare cases,the movements may occur as the dominant symptoms with only very limitedawareness of the urge to move.

In most cases, the cause of RLS is unknown. Such idiopathic disease canbe familial and, if so, is transmitted in an autosomal dominant fashion.Progressive decrease in age at onset with subsequent generations hasbeen described in some families. Patients with familial RLS tend to havean earlier age at onset and slower progression. Despite the use ofdopaminergic agents to treat RLS, the genes involved in dopaminergicneurotransmission were found to have no influence on RLS [Neurol., 57,1304-1306 (2001)].

Associated Features of RLS

RLS symptoms can cause difficulty in falling and staying asleepresulting in abnormal tiredness during waking hours. Chronic sleepdeprivation and its resultant daytime sleepiness can affect thepatient's ability to work, participate in social activities, and partakein recreational pastimes and can cause mood swings, which can affecttheir personal relationships.

RLS may be the result of another condition, which, when present, worsensthe underlying RLS. This is called secondary RLS. During pregnancy,particularly during the last few months, up to 15% of women develop RLS.After delivery, their symptoms often vanish. Other causes include thefollowing. Deficiency of iron, folate, B-12 or magnesium. Iron, folateand B-12 deficiencies can result in anemia. Magnesium deficiency is rareexcept in the presence of unusual diets. RLS can be the initial symptomof iron deficiency. Polyneuropathy can also lead to RLS. Polyneuropathycan be caused by alcohol abuse, amyloidosis, diabetes mellitus,lumbosacral radiculopathy, Lyme disease, rheumatoid arthritis, uremia orvitamin B-12 deficiency. Gastric surgery, which can lead tomal-absorption of foods. Chronic obstructive pulmonary disease (COPD)which can lead to changes in blood chemistry such as acidosis oralkalosis, low oxygen saturation, or retention of carbon dioxide. Thesechanges in the blood chemistry can, in turn, irritate the peripheralnerves and result in RLS. Chronic venous insufficiency or varicoseveins. Intake of certain drugs such as alcohol, caffeine,anticonvulsants, antidepressants, beta blockers, lithium or certainmajor tranquilizing agents. Abrupt withdrawal from certain drugs such asvasodilators, sedatives or antidepressants. Myelopathy or myelitis.Hypothyroidism or hyperthyroidism. Hypoparathyroidism orhyperparathyroidism. Acute intermittent porphrya. Liver failure. Cancer.

Though RLS is diagnosed most often in people in their middle years, manyindividuals with RLS, particularly those with primary RLS, can tracetheir symptoms back to childhood. These symptoms may have been calledgrowing pains or the children may have been thought to be hyperactivebecause they had difficulty sitting quietly.

No laboratory test exists that can confirm a diagnosis of RLS. However,a thorough physical examination, including the results of necessarylaboratory tests, can reveal temporary disorders, such as irondeficiency, that may be associated with RLS. Some patients will requirean overnight testing of sleep to determine other causes of their sleepdisturbance.

Treatment

If an underlying iron or vitamin deficiency is found to be the cause ofa patient's restless legs, supplementing with iron, vitamin B12, orfolate (as indicated) may be sufficient to relieve the symptoms. Currentrecommendations include checking a serum ferritin level (to evaluateiron-storage status) and supplementing with iron if the ferritin levelis less than 50 μg/L. Patients with varicose veins have been found tobenefit from use of sclerosing agents. Those with uremia may have reliefafter kidney transplantation or correction of anemia witherythropoietin.

The use of some medications seems to worsen the symptoms of RLS. Thesedrugs include calcium-channel blockers, most antinausea medications,some cold and allergy medications, major tranquilizers, phenytoin, andmost antidepressants.

Unfortunately, in many cases, the symptoms of RLS either initially donot resolve with the treatment of underlying disorders and theimplementation of lifestyle changes or, over time, progress so thatrelief is insufficient with these methods. In either case, the use ofmedications may become necessary.

No drugs have been approved by the U.S. Food and Drug Administration forthe treatment of RLS, but several drugs have undergone clinical studiesin RLS and have been approved for other conditions. These medicationsfall into four main classes-dopaminergic agents, sedatives, painrelievers, and anticonvulsants. Each drug or class of drugs has its ownbenefits, limitations, and side-effect profile. The choice of medicationis dependent upon the timing and severity of symptoms. Generally,treatment begins with a low dose taken an hour or two before bedtime. Iftolerance to one drug develops, another class of drugs may besubstituted.

Dopaminergic Agents

The primary and first-line treatment for RLS is with a dopaminergicagent [Expert Opin. Investig. Drugs, 11, 501-514 (2002); Neurol.,58(Suppl. 1), S87-S92 (2002); and Danek et al. In NeurologicalDisorders: Course and Treatment Academic Press, pp. 819-823 (1996)].Involvement of altered activity of dopaminergic diencephalic spinalneurons that originate in A11 region [Brain Res., 342, 340-351 (1985)].

Although dopaminergic agents are used to treat Parkinson's disease, RLSis not a form of Parkinson's disease [J. Neurol. Sci., 196, 33-36(2002)]. All of these drugs should be started at low doses and increasedvery slowly to decrease potential side effects. Due to the disablingside effects associated with long-term dopaminergic activation, chronicuse of this class of drugs in RLS has not been adopted.

A variety of dopaminergic agents have been described for treating RLS.These include carbidopa, levodopa, carbidopa with levodopa (Sinemet),ropinerole, pramipexole, cabergoline, entacapone and, Piribedil [Mov.Dis., 17, 421 (2002); Mov. Dis., 16, 579-581 (2001); Eur. Neurol.,46(suppl 1), 24-26 (2001); U.S. Pat. Nos. 6,194,445; 6,114,326;6,001,861; 5,945,424; and U.S. patent application No. 2001/0029262].

Dopaminergic agents can cause the side effect known as augmentation orrebound. Augmentation comprises an earlier onset of symptoms in theevening than before treatment, appearance of symptoms during the day,involvement of other body parts and an increased severity of symptoms.The only recourse is to stop taking the drug. Other side effects includenausea, dizziness, somnolence, insomnia, constipation, posturalhypotension, asthenia and hallucination.

Sedatives

Sedative agents are most effective for relieving the nighttime symptomsof RLS. They are used either at bedtime in addition to a dopaminergicagent or for individuals who have primarily nighttime symptoms. The mostcommonly used sedative is clonazepam (Klonopin). Other suggestedmedications such as anti-histamines and NK1-receptor antagonists mayfunction via their sedative effect.

Pain Relievers

Pain-relieving drugs are used most often for people with severerelentless symptoms of RLS. Some examples of medications in thiscategory include codeine, Darvon or Darvocet (propoxyphene); Dolophine(methadone); Percocet (oxycodone); Ultram (tramadol); and Vicodin(hydrocodone). Opioids have been found to be the most effective atrelieving symptoms, and relief has been found with intrathecal deliveryof morphine or bupivacaine [Acta Anaesthesiol. Scand., 46, 114-117(2002)]. Opioids are potent suppressors of RLS and PLMS, but the risksof abuse and addiction limit their use. Side effects and adversereactions include dizziness, sedation, nausea, vomiting, constipation,hallucination and headache.

Anticonvulsants

These drugs are particularly effective for some, but not all, patientswith marked daytime symptoms, particularly people who have painsyndromes associated with their RLS. Gabapentin (Neurontin) is theanticonvulsant that has shown the most promise in treating the symptomsof RLS [Neurol., 57, 1717-1719 (2001)].

Other Therapies

Other suggested treatments include transcutaneous electrical nervestimulation, conditioning therapy, and various procedures to reduceincompetent veins, but none of these ancillary treatments has beenclearly established to be effective [Health Technol. Assess., 1, 1-135(1997); Sleep, 19, 442-444 (1996); and Dermatol. Surg., 21, 328-332(1995)].

In particular, the Edinburgh vein study found that most lower-limbsymptoms (including RLS) probably have a nonvenous cause and surgicalintervention (i.e., sclerotherapy or “vein stripping”) is unlikely toalleviate the symptoms [Brit. Med. J., 318, 353-35 (1999)]. One groupadvocates medical therapy for what they call “hypotonic phlebopathy” (amild form of venous insufficiency), but their clinical descriptioncoincides with the symptoms of RLS almost perfectly [MinervaCardioangiol., 48, 277-285 (2000)].

Additional pharmaceutical agents have been proposed to treat RLS. Theseinclude 5HT antagonists; α₂ antagonists such as Mirtazapine;NK1-receptor antagonists; anti-histamines; and an herbal extract ofValeriana [Neurol., 53, 1154 (1999); U.S. Pat. Nos. 6,346,283;6,329,401; 6,319,927; 6,281,207; 6,214,837; and U.S. patent applicationNos. 2002/0035057; 2001/0034320; 2002/0010201]. Mirtazapine, however,may cause RLS [Psych. Clin. Neurosci., 56, 209-210 (2002)].

Children

Recent literature also points toward an association between RLS andsymptoms of attention-deficit hyperactivity disorder [Sleep, 25, 213-218(2002)]. A few case reports and one case series have assessed treatmentspecific to children. These case reports have indicated individualresponses to strict limit-setting in enforcing the child's sleepschedule, restricting caffeine consumption, and using medications suchas clonazepam, carbidopa/levodopa, pergolide, or clonidine [PicchiettiIn Wilson, ed. Sleep thief: restless legs syndrome. Orange Park, Fla.:Galaxy Books pp. 82-94 (1996); Pediatr. Neurol., 22, 182-186 (2000);Sleep Res., 22, 70 (1993); Pediatr Neurol., 11, 241-245 (1994); andSleep, 22, 297-300 (1999)].

Benzodiazepines, anticonvulsants, alpha-adrenergic agents, and opioidshave been extensively used in children with disorders other than RLS, ashas chronic use of levodopa for dopa-responsive dystonia [J. Am. Acad.Child Adolesc. Psych., 33, 424-426 (1994); and Neurol., 41, 174-181(1991)]. An open-label trial of pergolide in the treatment of RLS infive children with RLS found that not only the sleep parameters, butalso the children's scores of attention and impulsivity, improved[Pediatr. Neurol., 22, 182-186 (2000)].

PLMS

About 80% of patients with RLS have unilateral or bilateral periodiclimb movements of sleep (PLMS), also called nocturnal myoclonus.Patients without RLS also experience PLMS. These movements arestereotyped, repetitive, slow flexion of the limbs (legs alone or legsmore than arms) during the early stages of sleep. The movements occursemirhythmically at intervals of 5 to 60 seconds and last about 1.5 to2.5 seconds. In the lower limbs, repetitive dorsi flexion of the big toewith fanning of the small toes is seen, along with flexion of theankles, knees and thighs. Arm movements usually consist of the flexionof the forearm in combination with the wrist. There can benight-to-night variability in the number of movements.

PLMS can occur while patients are awake and are called dyskinesias. Suchdyskinesias are uncommon but can occur in up to 50% or RLS patients.

PLMS increases with age. Thirty five percent or more of people aged 65and older experience PLMS. PLMS also occurs in younger people, thoughless commonly. Men and women are equally affected. The exact cause ofPLMS is still unknown. The underlying mechanisms probably involvefactors in the nervous system, although studies have not revealed anyconsistent abnormalities.

PLMS are not considered medically serious. They can, however, beimplicated as a contributing factor in chronic insomnia and/or daytimefatigue because they may cause awakenings during the night.Occasionally, PLMS may be an indicator of a serious medical conditionsuch as kidney disease, diabetes or anemia.

A number of medications have been shown to be effective in treatingPLMS, but treatment is only necessary when PLMS are accompanied byrestless legs (RLS), insomnia or daytime fatigue.

Adenosine A_(2A) Receptors

Adenosine is known to act via four major receptor subtypes, A₁, A_(2A),A_(2B), A₃, which have been characterized according to their primarysequences [Pharmacol. Rev., 46, 143-156 (1994)]. Adenosine A_(2A)receptors are abundant in the caudate-putamen, nucleus accumbens, andolfactory tubercle in several species [Brain Res., 519, 333-337 (1990)].A variety of A_(2A) receptor antagonists have been synthesized (U.S.Pat. Nos. 6,262,106; 6,222,035; 6,197,788; 5,756,735; 5,703,085;5,670,498; 5,565,460; and 5,484,920).

In the caudate-putamen, adenosine A_(2A) receptors are localized onseveral neurons and have been shown to modulate the neurotransmission ofγ-aminobutyric acid (GABA), acetylcholine and glutamate [J. Neurochem.,66, 1882-1888 (1996); J. Neurosci., 16, 605-611 (1996); Neuroscience,100, 53-62 (2000); Trends Pharmacol. Sci., 18, 338-344 (1997); andBiosci. Biotechnol. Biochem., 65, 1447-1457 (2001)]. These actions ofthe A_(2A) receptor contribute to the control of motor behavior sinceA_(2A) receptor agonists inhibit locomotor activity and induce catalepsyin rodents [Adv. Neurol., 80, 121-123 (1999); and Psychopharmacology,147, 90-95 (1999)]. In contrast, adenosine A_(2A) receptor antagonistsprevent the motor disturbances of dopamine D₂ receptor null mice [J.Neurosci., 20, 5848-5852 (2000)].

A_(2A) receptor antagonists have been evaluated in parkinsonian monkeysand found to be effective at treating symptoms of Parkinson's disease[Ann. Neurol., 43, 507-513 (1998); NeuroReport, 9, 2857-2860 (1998); andExp. Neurol., 162, 321-327 (2000)]. It was demonstrated that theadenosine A_(2A) receptor antagonist KW-6002 exhibits antiparkinsonianactivity without producing hyperactivity and provoking dyskinesia[Neurology, 52, 1673-1677 (1999)].

More recently, the neuroprotective effect of an adenosine A_(2A)receptor antagonist KW-6002 has been demonstrated in MPTP-induceddopaminergic neurodegeneration [J. Neurochem., 80, 262-270 (2002); andJ. Neurosci., 21, RC143(1-6) (2001)].

SUMMARY OF THE INVENTION

The present invention relates to methods of treating restless legssyndrome or related disorders by administering a pharmaceutical agentcontaining a therapeutically effective amount of an adenosine A_(2A)receptor antagonist to a patient in need thereof. The present inventionalso relates to use of an adenosine A_(2A) receptor antagonist formanufacturing a therapeutic agent for treatment of restless legssyndrome as well as to therapeutic agents for restless legs syndromecomprising an adenosine A_(2A) receptor antagonist.

Preferably the adenosine A_(2A) receptor antagonist is a xanthinederivative or a pharmaceutically acceptable salt thereof. Morepreferably, the adenosine A_(2A) receptor antagonist is a xanthinederivative or a pharmaceutically acceptable salt thereof described indetail herein.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the following (1) to (26).

(1) A method of treating restless legs syndrome, comprisingadministrating an effective amount of at least one adenosine A_(2A)receptor antagonist to a patient in need thereof.

(2) The method of treating restless legs syndrome according to the above(1) wherein the adenosine A_(2A) receptor antagonist is a xanthinederivative or a pharmaceutically acceptable salt thereof.

(3) The method of treating restless legs syndrome according to the above(2) wherein the xanthine derivative is represented by the followingformula (I):

wherein R¹, R², and R³ independently represent hydrogen, lower alkyl,lower alkenyl, or lower alkynyl; R⁴ represents cycloalkyl, —(CH₂) —R⁵(in which R⁵ represents substituted or unsubstituted aryl, or asubstituted or unsubstituted heterocyclic group; and n is an integer of0 to 4) or

{in which Y¹ and Y² independently represent hydrogen, halogen or loweralkyl; and Z represents substituted or unsubstituted aryl, or

(in which R⁶ represents hydrogen, hydroxy, lower alkyl, lower alkoxy,halogen, nitro or amino; and m represents an integer of 1 to 3)}; and X¹and X² independently represent O or S.(4) The method of treating restless legs syndrome according to the above(2) wherein the xanthine derivative is represented by the followingformula (I-A):

wherein R^(1a) and R^(2a) independently represent methyl or ethyl;R^(3a) represents hydrogen or lower alkyl; and Z^(a) represents

(in which at least one of R⁷, R⁸ and R⁹ represents lower alkyl or loweralkoxy and the others represent hydrogen; R¹⁰ represents hydrogen orlower alkyl) or

(in which R⁶ and m have the same meanings as defined above,respectively).(5) The method of treating restless legs syndrome according to the above(2) wherein the xanthine derivative is represented by the followingformula (I-B):

wherein R^(1b) and R^(2b) independently represent hydrogen, propyl,butyl, lower alkenyl or lower alkynyl; R^(3b) represents hydrogen orlower alkyl; Z^(b) represents substituted or unsubstituted naphthyl, or

(in which R⁶ and m have the same meanings as defined above,respectively); and Y¹ and Y² have the same meanings as defined above,respectively.(6) The method of treating restless legs syndrome according to the above(2) wherein the xanthine derivative is(E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methylxanthine.(7) The method of treating restless legs syndrome according to the above(1) wherein the adenosine A_(2A) receptor antagonist is a compoundrepresented by the formula (II):

wherein R¹¹ represents substituted or unsubstituted aryl, or asubstituted or unsubstituted heterocyclic group; R¹² representshydrogen, halogen, lower alkyl, substituted or unsubstituted aryl, or asubstituted or unsubstituted heterocyclic group; R¹³ representshydrogen, halogen or X²R¹⁴ (in which X² represents O or S; and R¹⁴represents substituted or unsubstituted lower alkyl, substituted orunsubstituted aryl, a substituted or unsubstituted heterocyclic group,or substituted or unsubstituted aralkyl); and Q² represents hydrogen or3,4-dimethoxybenzyl {e.g.5-amino-7-(4-benzoylpiperazinyl)-2-(2-furyl)[1,2,4]triazolo[1,5-c]pyrimidine},or a pharmaceutically acceptable salt thereof.(8) The method of treating restless legs syndrome according to the above(1) wherein the adenosine A_(2A) receptor antagonist is a compoundrepresented by the formula (III):

wherein R¹⁵ represents substituted or unsubstituted aryl, or substitutedor unsubstituted heteroaryl; R¹⁶ represents hydrogen, halogen,substituted or unsubstituted lower alkyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl; m3 and n3 areindependently an integer of 0 to 4; Q³ represents hydrogen or3,4-dimethoxybenzyl; R²⁰ represents hydrogen, halogen, hydroxy, orsubstituted or unsubstituted lower alkyl; R¹⁷ represents hydroxy,hydroxy-substituted lower alkyl, substituted or unsubstituted loweralkoxy, or imidazo[1,2-a]pyridyl; and R¹⁸ and R¹⁹ independentlyrepresent hydrogen, substituted or unsubstituted lower alkyl, orsubstituted or unsubstituted aryl; or R¹⁸ and R¹⁹ are combined togetherwith an adjacent carbon atom to form a substituted or unsubstitutedcycloalkyl {e.g.5-amino-2-(2-furyl)-7-(4-(2-hydroxy-2-methylpropyl)piperazinyl)[1,2,4]triazolo[1,5-c]pyrimidine},or a pharmaceutically acceptable salt thereof.(9) The method of treating restless legs syndrome according to the above(1) wherein the adenosine A_(2A) receptor antagonist is a compoundrepresented by the formula (IV):

wherein Z⁴ represents O or S; and R²¹ represents Ph—(CH₂)_(n4)Y⁴ (inwhich Ph represents phenyl unsubstituted or substituted with halogen orlower alkyl; Y⁴ is a single bond, O or S; and n4 is an integer of 0 to5) {e.g.7-amino-2-(2-furyl)-5-phenoxy[1,2,4]-triazolo[1,5-a]pyrimidine}, or apharmaceutically acceptable salt thereof.(10) The method of treating restless legs syndrome according to theabove (1) wherein the adenosine A_(2A) receptor antagonist is a compoundrepresented by the formula (V):

wherein R²² represents hydrogen, substituted or unsubstituted loweralkyl, or substituted or unsubstituted lower alkanoyl; R²³ representshydrogen, substituted or unsubstituted lower alkyl, substituted orunsubstituted lower alkenyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstituted aralkyl,or a substituted or unsubstituted heterocyclic group; R²⁴ represents asubstituted or unsubstituted heterocyclic group; X⁵ represents a singlebond, O, S, S(O), S(O)₂ or NR²⁵ (in which R²⁵ represents hydrogen, orsubstituted or unsubstituted lower alkyl); and A represents N or CR²⁶(in which R²⁶ represents hydrogen, or substituted or unsubstituted loweralkyl), or a pharmaceutically acceptable salt thereof.(11) The method of treating restless legs syndrome according to theabove (1) wherein the adenosine A_(2A) receptor antagonist is a compoundrepresented by the formula (VI):

wherein R²⁷ represents substituted or unsubstituted aryl, or asubstituted or unsubstituted heterocyclic group; Y⁶ represents O, S orNR²⁹ (in which R²⁹ represents hydrogen, substituted or unsubstitutedlower alkyl, substituted or unsubstituted cycloalkyl, or substituted orunsubstituted aryl); R²⁸ represents hydrogen, substituted orunsubstituted lower alkyl, substituted or unsubstituted lower alkenyl,substituted or unsubstituted lower alkynyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted aralkyl, or a substituted or unsubstituted heterocyclicgroup; and B and the adjacent two carbon atoms are combined to form asubstituted or unsubstituted carbon ring or heterocyclic ring, or apharmaceutically acceptable salt thereof.(12) The method of treating restless legs syndrome according to theabove (1) wherein the adenosine A_(2A) receptor antagonist is a compoundrepresented by the formula (VII):

wherein R³⁰ represents substituted or unsubstituted lower alkyl, orsubstituted or unsubstituted aryl; W represents CH₂CH₂, CH═CH or CC; R³¹represents hydrogen, hydroxy, substituted or unsubstituted lower alkyl,substituted or unsubstituted amino, or a substituted or unsubstitutedheterocyclic group; R³² represents hydrogen, substituted orunsubstituted cycloalkyl, substituted or unsubstituted aryl, substitutedor unsubstituted heteroaryl, or substituted or unsubstituted loweralkenyl; and R³³ represents hydrogen, substituted or unsubstituted loweralkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted lower alkenyl, or substituted or unsubstituted loweralkynyl {e.g.4-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-fluorenyl]-2-methyl-3-butyn-2-ol},or a pharmaceutically acceptable salt thereof.(13) The method of treating restless legs syndrome according to theabove (1) wherein the adenosine A_(2A) receptor antagonist is a compoundrepresented by the formula (VIII):

wherein R³⁵ represents hydrogen or lower alkyl; R³⁶ and R³⁷independently represent hydrogen, substituted or unsubstituted loweralkyl, or substituted or unsubstituted aryl; and R³⁸, R³⁹, R⁴⁰, R⁴¹,R⁴², and R⁴³, independently represent hydrogen, substituted orunsubstituted lower alkyl, substituted or unsubstituted aryl, or asubstituted or unsubstituted heterocyclic group, or a pharmaceuticallyacceptable salt thereof.(14) The method of treating restless legs syndrome according to theabove (1) wherein the adenosine A_(2A) receptor antagonist is a compoundrepresented by the formula (IX):

wherein X⁹ represents CH or N; R⁴⁴ represents lower alkyl, substitutedor unsubstituted aryl, or a substituted or unsubstituted heterocyclicgroup; R⁴⁵ represents substituted or unsubstituted lower alkyl, or asubstituted or unsubstituted heterocyclic group; and R⁴⁶ representshydroxy, halogen, or substituted or unsubstituted lower alkyl {e.g.3-[2-(thiazol-2-ylmethyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine},or a pharmaceutically acceptable salt thereof.(15) The method of treating restless legs syndrome according to theabove (1) wherein the adenosine A_(2A) receptor antagonist is a compoundrepresented by the formula (X):

wherein X¹⁰ represents O or S; R⁴⁷ and R⁴⁸ independently representhydrogen, lower alkyl, aryl, hydroxy, alkoxy, cyano or nitro, ortogether form a carbonyl, oxime, imino or hydrazone group; R⁴⁹represents lower alkyl or aryl; and R⁵⁰, R⁵¹ and R⁵² independentlyrepresent hydroxy, halogen, substituted or unsubstituted lower alkyl,substituted or unsubstituted aryl, nitro, cyano or alkoxy {e.g.(2R)-2-(1-hydroxy-2-propylamino)thieno[3,2-d]pyrimidin-4-yl2-thienylmethanone}, or a pharmaceutically acceptable salt thereof.(16) The method of treating restless legs syndrome according to theabove (1) wherein the adenosine A_(2A) receptor antagonist is a compoundrepresented by the formula (XI):

wherein R⁵³ represents hydrogen, hydroxy, halogen, substituted orunsubstituted amino, or substituted or unsubstituted lower alkyl; R⁵⁴represents hydrogen, halogen, substituted or unsubstituted amino,substituted or unsubstituted lower alkynyl, substituted or unsubstitutedlower alkenyl, substituted or unsubstituted lower alkyl, or substitutedor unsubstituted lower alkoxy; R⁵⁵ represents substituted orunsubstituted lower alkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; Ar represents substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; and Q¹¹and W¹¹ independently represent N or CH {e.g.5-[6-amino-8-(3-fluorophenyl)-9H-9-purinyl]-1-methyl-1,2-dihydro-2-pyrimidine},or a pharmaceutically acceptable salt thereof.(17) The method of treating restless legs syndrome according to theabove (1) wherein the adenosine A_(2A) receptor antagonist is a compoundrepresented by the formula (XII):

wherein R⁵⁶ represents substituted or unsubstituted aryl, substituted orunsubstituted cycloalkenyl, or substituted or unsubstituted heteroaryl;X¹² represents a single bond or C(O); and R⁵⁷ represents substituted orunsubstituted lower alkyl, or a pharmaceutically acceptable saltthereof.(18) The method of treating restless legs syndrome according to theabove (1) wherein the adenosine A_(2A) receptor antagonist is a compoundrepresented by the formula (XIII):

wherein A¹³ represents a single bond, —S—, —N(R⁶³)— (in which R⁶³represents hydrogen or lower alkyl), —(CH₂)₂—, —CH═CH—, —CC— or —O—; X¹³and Y¹³ independently represents N or CH; R⁵⁸ represents hydrogen,substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl,halogen, cyano or cycloalkyl; R⁵⁹ represents hydrogen, halogen, cyano,nitro, substituted or unsubstituted lower alkyl, lower alkenyl, orsubstituted or unsubstituted aryl; R⁶⁰ represents lower alkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; and R⁶¹ and R⁶² independently represent hydrogen, orsubstituted or unsubstituted aryl, or a pharmaceutically acceptable saltthereof.(19) The method of treating restless legs syndrome according to theabove (1) wherein the adenosine A_(2A) receptor antagonist is a compoundrepresented by the formula (XIV):

wherein R⁶⁴ represents substituted or unsubstituted lower alkoxy,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R⁶⁵ and R⁶⁷ independently represent hydrogen, cyano orS(O)₂phenyl; R⁶⁶ represents hydrogen, halogen, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, orsubstituted or unsubstituted amino; and R⁶⁸ represents substituted orunsubstituted amino {e.g.2-(4,5-dihydro-furan-2-yl)-7-m-tolyl-[1,2,4]triazolo[1,5-a]pyridine-5-ylamine},or a pharmaceutically acceptable salt thereof.(20) The method of treating restless legs syndrome according to theabove (1) wherein the adenosine A_(2A) receptor antagonist is a compoundrepresented by the formula (XV):

wherein A¹⁵ represents substituted or unsubstituted aryl, or substitutedor unsubstituted heteroaryl; B¹⁵ represents substituted or unsubstitutedheteroaryl; R⁶⁹ and R⁷⁰ independently represent hydrogen, or substitutedor unsubstituted amino, or a pharmaceutically acceptable salt thereof.(21) The method of treating restless legs syndrome according to theabove (1) wherein the adenosine A_(2A) receptor antagonist is a compoundrepresented by the formula (XVI):

wherein R⁷¹ represents cyano, carboxy, or substituted or unsubstitutedcarbamoyl; R⁷² represents hydrogen, hydroxy, substituted orunsubstituted lower alkoxy, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; and R⁷³ and R⁷⁴ independentlyrepresent substituted or unsubstituted aryl, or a substituted orunsubstituted heterocyclic group, or a pharmaceutically acceptable saltthereof.(22) The method of treating restless legs syndrome according to theabove (1) wherein the adenosine A_(2A) receptor antagonist is a compoundrepresented by the formula (XVII):

wherein R⁷⁵ represents hydrogen, hydroxy, halogen, lower alkyl, loweralkoxy, benzyloxy or OCF₃; R⁷⁶ and R⁷⁷ independently represent hydroxy,halogen, lower alkyl or lower alkoxy; R⁷⁸ represents hydrogen, halogen,lower alkyl, lower alkenyl, carboxy, lower alkanoyl, loweralkoxycarbonyl, (CH₂)_(n17)—OH (in which n17 is an integer of 0 to 4),substituted or unsubstituted phenyl, 2,3-dihydro-1H-indolyl, azepan-1-ylor 1,4-oxazepan-4-yl; R⁷⁹ represents substituted or unsubstitutedphenyl; and X¹⁷ represents O, S or 2H {e.g.4-hydroxymethyl-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)benzamide}, or apharmaceutically acceptable salt thereof.(23) The method of treating restless legs syndrome according to theabove (1) wherein the adenosine A_(2A) receptor antagonist is(−)-(11S,2′R)-α-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol or a pharmaceutically acceptablesalt thereof.(24) Use of the adenosine A_(2A) receptor antagonist described in anyone of the above (1) to (23) for manufacturing a therapeutic agent forrestless legs syndrome.(25) A therapeutic agent for restless legs syndrome comprising theadenosine A_(2A) receptor antagonist described in any one of the above(1) to (23).(26) A method of treating nocturnal myoclonus, comprising administratingan effective amount of the adenosine A_(2A) receptor antagonistdescribed in any one of the above (1) to (23) to a patient in needthereof.

The adenosine A_(2A) receptor antagonist used in the method of thepresent invention is not limited as long as it has A_(2A) receptorantagonistic activity. A_(2A) receptor antagonistic activity includesactivity to inhibit, suppress or cause the cessation of at least oneadenosine-mediated biological activity by, e.g., binding to adenosineA_(2A) receptors, or interfering with or preventing the binding ofadenosine to the receptor. Examples of the adenosine A_(2A) receptorantagonist include compounds disclosed in U.S. Pat. No. 5,484,920, U.S.Pat. No. 5,703,085, WO 92/06976, WO 94/01114, U.S. Pat. No. 5,565,460,WO 98/42711, WO 00/17201, WO 99/43678, WO 99/26627, WO 01/92264, WO99/35147, WO 00/13682, WO 00/13681, WO 00/69464, WO 01/40230, WO01/02409, WO 01/02400, EP 1054012, WO 01/62233, WO 01/17999, WO01/80893, WO 02/14282, WO 01/97786, or the like. More specifically,examples include compounds represented by the above-described formula(I), (I-A), (I-B), or (II) to (XVII),(−)-(11S,2′R)-α-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol,and pharmaceutically acceptable salts thereof.

A preferred adenosine A_(2A) receptor antagonist used in the method ofthe present invention is(E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methylxanthine (hereinafterreferred to Compound A) shown below.

In the definition of each group of formulas (I), (I-A), (I-B), and (II)to (XVII), the lower alkyl and the lower alkyl moiety of the loweralkoxy, hydroxy-substituted lower alkyl, lower alkanoyl, and loweralkoxycarbonyl include straight-chain or branched alkyl groups having 1to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl andoctyl. The lower alkenyl includes straight-chain or branched alkenylgroups having 2 to 8 carbon atoms, such as vinyl, allyl, methacryl,crotyl, 3-butenyl, 2-pentenyl, 4-pentenyl, 2-hexenyl, 5-hexenyl,2-heptenyl and 2-octenyl. The lower alkynyl includes straight-chain orbranched alkynyl groups having 2 to 8 carbon atoms, such as ethynyl,propargyl, 2-butynyl, 3-butynyl, 2-pentynyl, 4-pentynyl, 2-hexynyl,5-hexynyl, 4-methyl-2-pentynyl, 2-heptynyl and 2-octynyl. The cycloalkylincludes cycloalkyl groups having 3 to 8 carbon atoms, such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl. The cycloalkenyl includes cycloalkenyl groups having 4 to 8carbon atoms, such as cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl and cyclooctenyl. The aryl includes those having 6 to 14carbon atoms, such as phenyl and naphthyl. The aralkyl includes thosehaving 7 to 15 carbon atoms, such as benzyl, phenethyl, benzhydryl andnaphthylmethyl. Examples of the heteroaryl are furyl, thienyl, pyrrolyl,pyranyl, thiopyranyl, pyridyl, thiazolyl, imidazolyl, pyrimidyl,pyridazinyl, pyridazinoyl, triazinyl, indolyl, quinolyl, purinyl andbenzothiazolyl. Examples of the heterocyclic group are pyrrolidinyl,piperidino, piperidinyl, piperazinyl, morpholino, morpholinyl,thiomorpholino, thiomorpholinyl, homopiperidino, homopiperidinyl,homopiperazinyl, tetrahydropyridinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, tetrahydrofuranyl, tetrahydropyranyl,imidazolidinyl, thiazolidinyl and oxazolidinyl in addition to groupslisted as examples of the heteroaryl. The halogen includes fluorine,chlorine, bromine and iodine. The carbon ring formed by combining B andthe adjacent two carbons include those having 4 to 8 carbon atoms and atleast one double bond, such as cyclobutene, cyclopentene, cyclohexene,cycloheptene and cyclooctene. Examples of the heterocyclic ring formedby combining B and the adjacent two carbons are pyrrole, pyrane,thiopyrane, pyridine, thiazole, imidazole, pyrimidine, triazine, indole,quinoline, benzothiazole, pyrroline, tetrahydropyridine,tetrahydropyrazine, tetrahydroquinoline and tetrahydroisoquinoline.

The substituted lower alkyl, the substituted lower alkoxy, thesubstituted lower alkanoyl and the substituted lower alkenyl each have,for example, 1 to 3 independently selected substituents. Examples of thesubstituents are hydroxy, substituted or unsubstituted lower alkoxy,halogen, nitro, amino, lower alkylamino, di(lower alkyl) amino,trifluoromethyl, trifluoromethoxy, benzyloxy, phenyl and phenoxy. Thelower alkyl and the alkyl moiety of the lower alkoxy, lower alkylaminoand di(lower alkyl)amino have the same meaning as the lower alkyldefined above. The halogen has the same meaning as the halogen definedabove. Examples of the substituent of the substituted lower alkoxy arehydroxy, lower alkoxy, halogen, amino, azide, carboxy and loweralkoxycarbonyl. The lower alkyl moiety of the lower alkoxy and loweralkoxycarbonyl has the same meaning as the lower alkyl defined above,and the halogen has the same meaning as the halogen defined above.

The substituted aryl, the substituted naphthyl, the substituted phenyl,the substituted aralkyl, the substituted heterocyclic ring, thesubstituted heteroaryl, the substituted cycloalkyl, the substitutedcycloalkenyl, the substituted carbon ring formed by combining B and theadjacent two carbons, and the substituted heterocyclic ring formed bycombining B and the adjacent two carbons each have, for example, 1 to 4independently selected substituents. Examples of the substituents arelower alkyl, hydroxy, substituted or unsubstituted lower alkoxy,halogen, nitro, amino, lower alkylamino, di(lower alkyl)amino,trifluoromethyl, trifluoromethoxy, benzyloxy, phenyl and phenoxy. Thelower alkyl and the alkyl moiety of the lower alkoxy, lower alkylaminoand di(lower alkyl)amino have the same meaning as the lower alkyldefined above. The halogen has the same meaning as the halogen definedabove. Examples of the substituent of the substituted lower alkoxy arehydroxy, lower alkoxy, halogen, amino, azide, carboxy and loweralkoxycarbonyl. The lower alkyl moiety of the lower alkoxy and loweralkoxycarbonyl has the same meaning as the lower alkyl defined above,and the halogen has the same meaning as the halogen defined above.

The substituted amino and the substituted carbamoyl each have 1 or 2independently selected substituents. Examples of the substituents aresubstituted or unsubstituted lower alkyl, or substituted orunsubstituted lower alkoxy. The lower alkyl and the alkyl moiety of thelower alkoxy have the same meaning as the lower alkyl defined above.Examples of the substituent of the substituted lower alkyl and thesubstituted lower alkoxy are hydroxy, lower alkoxy, halogen, amino,azide, carboxy and lower alkoxycarbonyl. The lower alkyl moiety of thelower alkoxy and lower alkoxycarbonyl has the same meaning as the loweralkyl defined above, and the halogen has the same meaning as the halogendefined above.

Hereinafter, compounds represented by formulas (I), (I-A), (I-B), and(II) to (XVII) will be referred to as Compounds (I), (I-A), (I-B), and(II) to (XVII), respectively.

The pharmaceutically acceptable salts of Compounds (I), (I-A), (I-B),and (II) to (XVII) include pharmaceutically acceptable acid additionsalts, metal salts, ammonium salts, organic amine addition salts andamino acid addition salts.

The pharmaceutically acceptable acid addition salts include inorganicacid addition salts such as hydrochloride, sulfate, nitrate andphosphate, and organic acid addition salts such as acetate, maleate,fumarate and citrate; the pharmaceutically acceptable metal saltsinclude alkali metal salts such as sodium salt and potassium salt,alkaline earth metal salts such as magnesium salt and calcium salt,aluminium salt and zinc salt; the pharmaceutically acceptable ammoniumsalts include ammonium and tetramethylammonium; the pharmaceuticallyacceptable organic amine addition salts include addition salts withmorpholine or piperidine; and the pharmaceutically acceptable amino acidaddition salts include addition salts with lysine, glycine orphenylalanine.

Compounds (I), (I-A), (I-B), and (II) to (XVII), and pharmaceuticallyacceptable salts thereof can be produced in accordance with themethodology described in U.S. Pat. No. 5,484,920, U.S. Pat. No.5,703,085, WO 92/06976, WO 94/01114, U.S. Pat. No. 5,565,460, WO98/42711, WO 00/17201, WO 99/43678, WO 99/26627, WO 01/92264, WO99/35147, WO 00/13682, WO 00/13681, WO 00/69464, WO 01/40230, WO01/02409, WO 01/02400, EP 1054012, WO 01/62233, WO 01/17999, WO01/80893, WO 02/14282, WO 01/97786 or the like.

Pharmaceutical compositions for administration according to the presentinvention comprise at least one adenosine A_(2A) receptor antagonist asactive ingredient(s) optionally combined with a pharmaceuticallyacceptable carrier(s). These compositions can be administered by anymeans that achieve their intended purposes. Amounts and regimens for theadministration of a composition according to the present invention canbe readily determined by those with ordinary skill in the art intreating patients suffering from RLS.

The pharmaceutical compositions described herein can be administered byany suitable method including, without limitation, orally; intranasally;intrapulmonarily; parenterally, such as subcutaneously, intravenously,intramuscularly, intraperitoneally; intraduodenally; transdermally; orbuccally.

The dosage administered is an effective amount and depends upon the age,health and weight of the patient, type of previous or concurrenttreatment, if any, frequency of treatment, and the nature of the effectdesired. Several factors are typically taken into account whendetermining an appropriate dosage. These factors include age, sex andweight of the patient, the condition being treated, the severity of thecondition and the form of the drug being administered.

An “effective amount” is an amount sufficient to effect a beneficial ordesired clinical result. An effective amount can be administered in oneor more doses. In terms of treatment, an effective amount is amount thatis sufficient to palliate, ameliorate, stabilize, reverse or slow theprogression of the disease or disorder, or otherwise reduce thepathological consequences of the disease or disorder. The effectiveamount is generally determined by the physician on a case-by-case basisand is within the skill of one in the art.

In addition to the active ingredient(s), the pharmaceutical compositionsaccording to the present invention can also contain a suitablepharmaceutically acceptable carrier such as an excipient thatfacilitates processing of the active ingredient(s) into apharmaceutically acceptable preparation. Preferably, the preparations,particularly those preparations which can be administered orally andwhich can be used for the preferred type of administration, such astablets, troches and capsules, and also preparations which can beadministered rectally, such as suppositories, as well as suitablesolutions for administration by injection or oral administration,contain from about 0.1 to 99 percent, preferably from about 20 to 85percent of active ingredient(s), together with the excipient. Liquidpreparations can, for example, be prepared by dissolving or dispersing acompound embodied herein in a liquid excipient, such as water, saline,aqueous dextrose, glycerol, or ethanol. The pharmaceutical compositioncan also contain other medicinal agent(s), pharmaceutical agent(s),carrier(s), or auxiliary substance(s) such as wetting or emulsifyingagent(s), or pH buffering agent(s).

Pharmaceutical compositions according to the present invention areadministered by a mode appropriate for the form of composition. Typicalroutes include subcutaneous, intramuscular, intraperitoneal,intradermal, oral, intranasal, and intrapulmonary (i.e., by aerosol).Pharmaceutical compositions according to the present invention for humanuse are typically administered orally.

Pharmaceutical compositions for oral, intranasal, or topicaladministration can be supplied in solid, semi-solid or liquid forms,including tablets, capsules, powders, liquids, and suspensions.Pharmaceutical compositions for injection can be supplied as liquidsolutions or suspensions, as emulsions, or as solid forms suitable fordissolution or suspension in liquid prior to injection. Foradministration via the respiratory tract, a preferred pharmaceuticalcomposition is one that provides a solid, powder, or liquid aerosol whenused with an appropriate aerosolizer device. Although not required,pharmaceutical compositions are preferably supplied in unit dosage formsuitable for administration of a precise amount. Also contemplated bythe present invention are slow release or sustained release forms,whereby relatively consistent levels of the active ingredient(s) areprovided over an extended period.

The adenosine A_(2A) receptor antagonists may preferably be administeredin an amount of from about 0.001 to about 20.0 mg per kilogram of bodyweight. A dosage range of from about 0.01 to about 10 mg per kilogram ofbody weight is more preferable. Since the adenosine A_(2A) receptorantagonists used in the present invention will eventually be clearedfrom the bloodstream, re-administration of the pharmaceuticalcompositions is indicated and preferred.

The adenosine A_(2A) receptor antagonists can be administered in amanner compatible with the dosage formulation and in such an amount aswill be therapeutically effective. Systemic dosages depend on the age,weight and conditions of the patient and on the administration route.

Pharmaceutical preparations useful in the methods according to thepresent invention are manufactured in a known manner. The preparation ofpharmaceutical compositions is conducted in accordance with generallyaccepted procedures for the preparation of pharmaceutical preparations[e.g., Remington's Pharmaceutical Sciences 18^(th) Edition (1990), E. W.Martin ed., Mack Publishing Co., Pa]. Depending on the intended use andmode of administration, it may be desirable to process the activeingredient further in the preparation of pharmaceutical compositions.Appropriate processing may include sterilizing, mixing with appropriatenon-toxic and non-interfering components, dividing into dose units, andenclosing in a delivery device.

The pharmaceutical preparations for oral use can be obtained bycombining the active ingredient(s) with solid excipient(s), optionallygrinding the resulting mixture, and processing the mixture of granules,after adding suitable auxiliarie(s), if desired or necessary, to obtaintablets.

Suitable excipients include fillers such as saccharides, for example,lactose, sucrose, mannitol or sorbitol; cellulose derivatives; zinccompounds; and/or calcium phosphates such as tricalcium phosphate orcalcium hydrogen phosphates; binders such as starch paste, using, forexample, maize starch, wheat starch, rice starch or potato starch;gelatin; tragacanth; and/or polyvinylpyrrolidone.

Auxiliaries include flow-regulating agents and lubricants, such assilica, talc, stearic acid or salts thereof, and/or polyethylene glycol.Tablet, caplet or capsule cores are provided with suitable coatingswhich, if desired, are resistant to gastric juices. For this purpose,concentrated saccharide solutions can be used, which can optionallycontain gum Arabic, talc, polyvinyl pyrrolidone, polyethylene glycoland/or titanium dioxide, lacquer solutions and suitable organic solventsor solvent mixtures. In order to produce coatings resistant to gastricjuices, i.e., enteric coatings, solutions of suitable cellulosepreparations such as acetylcellulose phthalate or hydroxypropyl methylcellulose phthalate are used. Dyes or pigments can be added to thetablets or coatings, for example, for identification or in order tocharacterize combinations of active compound doses.

Other pharmaceutical preparations, which can be used orally, includepush-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredient(s) in the form of granules,which can be mixed with filler(s) such as lactose, binders such asstarches, and/or lubricant(s) such as talc or magnesium stearate and,optionally, stabilizer(s). In soft capsules, the active ingredient(s)are preferably dissolved or suspended in suitable liquids, such as fattyoils or liquid paraffin. In addition, stabilizer(s) may be added.

The adenosine A_(2A) receptor antagonists of the present invention canalso be administered in the form of an implant when compounded with abiodegradable slow-release carrier. Alternatively, the activeingredients can be formulated as a transdermal patch for continuousrelease of the active ingredient(s). Methods of making implants andpatches are well known in the art [Remington's Pharmaceutical Sciences18^(th) Edition (1990), E. W. Martin ed., Mack Publishing Co., Pa; andKydonieus ed. (1992) Treatise on controlled drug delivery Marcel Dekker,NY].

The following non-limiting Examples, further illustrate the presentinvention. All references cited herein are hereby incorporated byreference.

Example 1 Animal Model, RLS Treatment with an A_(2A) Receptor Antagonist

Compound A, a novel potent adenosine A_(2A) receptor antagonist has beenproved efficacious in ameliorating Parkinsonian symptoms in animalmodels and in an early Phase II studies in patients with advancedParkinson's disease. The ability of Compound A to interact with themidbrain dopaminergic and GABAergic systems provides a basis fortreating RLS.

It is reported that bilateral 6-OHDA lesions into the A11 nucleuselicited behavioral correlates similar to clinical conditions of RLS,that is, increased average number of standing episodes and increasedtotal standing time [Ondo et al., Mov. Dis., 15, 154-158 (2000)].Notably, treatment of the lesioned animals with a dopamine agonist,pramipexole, subsequently resulted in fewer standing episodes and lesstotal standing time. These findings are consistent with what would beexpected in an animal model of RLS.

In order to determine the effectiveness of A_(2A) antagonists in the RLSanimal model system, the method according to Ondo et al. (2000) is used.Anesthetized rats are stereotaxically injected with approximately 8 μgof 6-OHDA dissolved in phosphate-buffered saline (PBS) containing0.01-0.05 w/v % ascorbic acid into both right and left A11 nuclei.Control rats are similarly injected with vehicle without 6-OHDA.

Two to 12 weeks after 6-OHDA or vehicle injection, animals are observedfor 30-120 minutes and their behaviors are scored in terms of number oftimes standing on two legs and total amount of time on two legs.Duration of total sleep time may also be measured. Introduction ofelectroencephalography or electromyography further helps elucidate thebehavior characteristics of the animals, lesioned or not. Effects ofpharmacological manipulation on the lesioned animals are subsequentlyassessed. Administration of adenosine A_(2A) receptor antagonistscounteracts the altered behaviors observed in the lesioned animals.Vehicle- or pramipexole-treatment lesioned animals serve as a negativeor positive control, respectively.

After the completion of behavioral tests and drug or control treatment,rats are sacrificed and their whole brains are removed. Coronal sectionsof diencephalic regions containing A11 groups are cut in a cryostat andthe sections obtained are subsequently processed to tyrosine hydroxylase(TH) immunohistochemistry. Stained sections are observed under the lightmicroscope to confirm the proper lesion of A11 nuclei. The results ofcontrols compared to A_(2A) antagonist are compared in light of thelesion results.

Example 2 Human Clinical Trial, RLS Treatment with an A_(2A) Antagonist

This study evaluates the efficacy of Compound A in RLS. A total of 45patients diagnosed with moderate to severe idiopathic RLS and PLMS areallocated into 3 groups. Patients who have failed to respond to one orcombined treatment are not eligible for this study. The baseline RLS andPLMS symptoms are evaluated by a patient-administered visual analogscale, the clinician's global impression scale (CGI), andpolysomnograph. Patients in the first group receive 5 mg Compound A,second group 20 mg, and third group 80 mg, once daily for 8 weeks.Weekly assessment is administered during the treatment period. Thevalues of the assessment at week 8 are compared to the baseline valueswith statistical analysis.

Example 3 Human Clinical Trial, RLS Treatment with an A_(2A) Antagonist

In order to assess the efficacy of a representative A_(2A) antagonist intreating RLS, a clinical trial was initiated and conducted in accordancewith standard procedures. Briefly, the total score in International RLSRating Scale (IRLSRS) and total PLMS index (polysomnography; PLMS indexrepresents the number of periodic limb movements per hour of sleep) ofthe patients were measured to evaluate the efficacy of Compound A in RLS[Understanding and Diagnosing Restless Legs Syndrome (2003), RestlessLegs Syndrome Foundation, 819 Second Street, SW Rochester, Minn. 55902].

Scoring for IRLSRS was made according to the following Instructions forExaminer (Maximum IRLSRS total score is 40).

The Examiner was instructed to have the patient rate his/her symptomsfor the following ten questions. The patient and not the examiner madethe ratings, but the examiner was available to clarify anymisunderstandings the patient may have had about the questions. Eitherthe examiner or the patient marked the answers on the form. In questions1, 2, 4, 5, 6, 9 and 10, the following scoring was used: (4) Verysevere; (3) Severe; (2) Moderate; (1) Mild; and (0) None.

1. Overall, how would you rate the RLS discomfort in your legs or arms?

2. Overall, how would you rate the need to move around

3. Overall, how much relief of your RLS arm or leg discomfort do you getfrom moving around?

(4) No relief

(3) Slight relief

(2) Moderate relief

(1) Either complete or almost complete relief

(0) No RLS symptoms and therefore question does not apply

4. Overall, how severe is your sleep disturbance from your RLS symptoms?

5. How severe is your tiredness or sleepiness from your RLS symptoms?

6. Overall, how severe is your RLS as a whole?

7. How often do you get RLS symptoms?

(4) Very severe (This means 6 to 7 days a week.)

(3) Severe (This means 4 to 5 days a week.)

(2) Moderate (This means 2 to 3 days a week.)

(1) Mild (This means 1 day a week or less.)

(0) None

8. When you have RLS symptoms, how severe are they on an average day?

(4) Very severe (This means 8 hours per 24 hour day or more.)

(3) Severe (This means 3 to 8 hours per 24 hour day.)

(2) Moderate (This means 1 to 3 hours per 24 hour day.)

(1) Mild (This means less than 1 hour per 24 hour day.)

(0) None

9. Overall, how severe is the impact of your RLS symptoms on yourability to carry out your daily affairs, for example carrying out asatisfactory family, home, social, school, or work life?

10. How severe is your mood disturbance from your RLS symptoms—forexample angry, depressed, sad, anxious, or irritable?

Patients diagnosed with idiopathic RLS were withheld from the medicationfrom the time of screening until the end of treatment. After taperingall RLS medications, patients were screened for eligibility. At Week −2,patients were admitted to the clinic on the night preceding the visitday to be adapted to the sleep environment of the laboratory. Afterscreening, IRLSRS total score and total PLMS index of the patients weremeasured on Day −1 in order to establish a baseline and to assess therange of RLS fluctuation. Only patients with moderate to severe RLS (15and more IRLSRS total scores) were enrolled in the study. And patientswho showed more than 35% fluctuation in IRLSRS and/or polysomnographybetween Week −1 visit and Day −1 visit (a base line) were not subjectedto further study.

Treatment with Compound A (80 mg, once a day) began on the day followingDay −1 visit and continued for the next 6 weeks. The last dose ofCompound A was taken on the day of Week 6 visit. At Week 8, patientsreceived RLS assessments (IRLSRS total score and total PLMS index). Theinhibition ratio for each score was calculated by the followingequation.Inhibition Ratio(%)={[(Score at Day−1)−(Score at Week 8)]/(Score atDay−1)}×100

The results are shown in Table 1 below.

TABLE 1 Baseline Inhibition (Day-1) Week 8 Ratio mean (SD) mean (SD) (%)IRLSRS 32.5 (4.39)   23 (8.04) 29.2 Total Score Total PLMS   45 (15.41)24.67 (23.89) 45.2 Index N = 4

As shown in Table 1, both IRLSRS total score and total PLMS indexdecreased at Week 8 from respective baseline values. That is, 80 mg ofCompound A once a day for 6 weeks resulted in relief of RLS symptoms andimprovement in patients with moderate to severe RLS. These results showfor the first time that the adenosine A_(2a) receptor antagonist iseffective in the treatment of RLS.

Certain embodiments of the present invention are described in thefollowing examples.

Example 1 Tablets

Tablets having the following composition are prepared in a conventionalmanner.

Compound A (40 g) is mixed with 286.8 g of lactose and 60 g of potatostarch, followed by addition of 120 g of a 10% aqueous solution ofhydroxypropyl cellulose. The resultant mixture is kneaded, granulated,and then dried by a conventional method. The granules are refined togive granules used to make tablets. After mixing the granules with 1.2 gof magnesium stearate, the mixture is formed into tablets eachcontaining 20 mg of the active ingredient by using a tablet maker (ModelRT-15, Kikusui) having pestles of 8 mm diameter.

The prescription is shown in Table 2.

TABLE 2 Compound A 20 mg Lactose 143.4 mg Potato Starch 30 mgHydroxypropyl Cellulose 6 mg Magnesium Stearate 0.6 mg 200 mg

Example 2 Capsules

Capsules having the following composition are prepared in a conventionalmanner.

Compound A (200 g) is mixed with 995 g of Avicel and 5 g of magnesiumstearate. The mixture is put in hard capsules No. 4 each having acapacity of 120 mg by using a capsule filler (Model LZ-64, Zanashi) togive capsules each containing 20 mg of the active ingredient.

The prescription is shown in Table 3.

TABLE 3 Compound A 20 mg Avicel 99.5 mg Magnesium Stearate 0.5 mg 120 mg

Example 3 Injections

Injections having the following composition are prepared in aconventional manner.

Compound A (1 g) is dissolved in 100 g of purified soybean oil, followedby addition of 12 g of purified egg yolk lecithin and 25 g of glycerinfor injection. The resultant mixture is made up to 1,000 ml withdistilled water for injection, thoroughly mixed, and emulsified by aconventional method. The resultant dispersion is subjected to asepticfiltration by using 0.2 μm disposable membrane filters, and thenaseptically put into glass vials in 2 ml portions to give injectionscontaining 2 mg of the active ingredient per vial.

The prescription is shown in Table 4.

TABLE 4 Compound A 2 mg Purified Soybean Oil 200 mg Purified Egg YolkLecithin 24 mg Glycerine for Injection 50 mg Distilled Water forInjection 1.72 ml 2.00 ml

1. A method of treating restless legs syndrome, comprising administeringan effective amount of at least one adenosine A2A receptor antagonist toa patient suffering from restless legs syndrome, which patient does nothave Parkinson's disease, wherein the adenosine A2A receptor antagonistis a xanthine derivative or a pharmaceutically acceptable salt thereof,wherein the xanthine derivative is represented by the following formula(I-A):

wherein R^(1a) and R^(2a) independently represent methyl or ethyl;R^(3a) represents hydrogen or lower alkyl; and Z^(a) represents

(in which at least one of R⁷, R⁸ and R⁹ represents lower alkyl or loweralkoxy and the others represent hydrogen; and R¹⁰ represents hydrogen orlower alkyl) or

(in which R⁶ represents hydrogen, hydroxy, lower alkyl, lower alkoxy,halogen, nitro or amino; and m represents an integer of 1 to 3).
 2. Themethod of treating restless legs syndrome according to claim 1, whereinthe xanthine derivative is(E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methylxanthine.
 3. A method oftreating nocturnal myoclonus, comprising administering an effectiveamount of at least one adenosine A2A receptor antagonist to a patientsuffering from nocturnal myoclonus, which patient does not haveParkinson's disease, wherein the adenosine A2A receptor antagonist is axanthine derivative or a pharmaceutically acceptable salt thereof,wherein the xanthine derivative is represented by the following formula(I-A):

wherein R^(1a) and R^(2a) independently represent methyl or ethyl;R^(3a) represents hydrogen or lower alkyl; and Z^(a) represents

(in which at least one of R⁷, R⁸ and R⁹ represents lower alkyl or loweralkoxy and the others represent hydrogen; and R¹⁰ represents hydrogen orlower alkyl) or

(in which R⁶ represents hydrogen, hydroxy, lower alkyl, lower alkoxy,halogen, nitro or amino; and m represents an integer of 1 to 3).
 4. Themethod of treating nocturnal myoclonus according to claim 3, wherein thexanthine derivative is(E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methylxanthine.